RESUMO
Chronic kidney disease (CKD) is associated with numerous metabolic and endocrine disturbances, including abnormalities of calcium and phosphate metabolism and an inflammatory syndrome. The latter occurs early in the course of CKD and contributes to the development and progression of vascular calcification. A few therapeutic strategies are today contemplated to target vascular calcification in patients with CKD: vitamin K2, calcimimetics and phosphate binders. However, none has provided complete prevention of vascular calcification and there is an urgent need for alternate efficient treatments. Recent findings indicate that tissue-nonspecific alkaline phosphatase (TNAP) may represent a very promising drug target due to its participation in mineralization by vascular smooth muscle cells. We report the synthesis of four levamisole derivatives having better inhibition property on TNAP than levamisole. Their IC50, Ki and water solubility have been determined. We found that the four inhibitors bind to TNAP in an uncompetitive manner and are selective to TNAP. Indeed, they do not inhibit intestinal and placental alkaline phosphatases. Survival MTT tests on human MG-63 and Saos-2 osteoblast-like cells have been performed in the presence of inhibitors. All the inhibitors are not toxic at concentrations that block TNAP activity. Moreover, they are able to significantly reduce mineralization in MG63 and Saos-2 osteoblast-like cells, indicating that they are promising molecules to prevent vascular calcification.
Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Levamisol/farmacologia , Tiofenos/farmacologia , Fosfatase Alcalina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Levamisol/síntese química , Levamisol/química , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
Two new heterocycles, pyrimido[4,5-c]carbazole and pyrimido[5,4-b]indole, were prepared in three steps from 3-aminocarbazole and 3-aminoindole, respectively. The key Friedel-Crafts intramolecular cyclization was realized under microwave irradiation using montmorillonite K-10 clay as a catalyst. The pyrimido[4,5-c]carbazole derivative shows significant micromolar IC(50) against cancer cell lines. Unlike similar carbazole and indolocarbazole compounds, the molecule does not interfere with topoisomerase activity.
Assuntos
Bentonita/química , Carbazóis/química , Guanidinas/química , Indóis/química , Catálise , Linhagem Celular Tumoral , Ciclização , HumanosRESUMO
In an effort to increase the structural diversity of pyrido[4,3,2-kl]acridines, compounds containing amino substituents on the A ring were synthesized. The key-reactions involve regioselective electrophilic aromatic substitutions. The methodology was applied to the synthesis of the extended angular octacycle 8, which conjugates the physicochemical and spectroscopic properties of the pyridoacridine skeleton with the ability of [1,10]phenanthroline ring for metal complexation. The 9-aminopyridoacridine 4 displays significant cytostatic activities against two cancer cell lines, and may be considered as a new lead in the search of active derivatives.